Chemokine is known as an endogeneous basic protein having leukocyte chemotactic and activating abilities and strong heparin-binding abilities. At present, it is considered that chemokine is related to not only the control of infiltration of specific leukocyte at the time of inflammations and immune responses but also the development and homing of lymphocyte under physiological conditions and migration of hemocyte precursor cells and somatic cells.
Differentiation, proliferation and cell death of hemocytes are controlled by various types of cytokine. In the living body, inflammations are found topically and differentiation, maturation and the like of lymphocytes are carried out at certain specified sites. That is, various necessary cells migrate into certain specified sites and accumulate therein to cause a series of inflammations and immune responses. Accordingly, migration of cells is also an indispensable phenomenon in addition to differentiation, proliferation and death of cells.
Migration of hemocytes in the living body starts firstly in the development stage by the shift of hematopoiesis started in the AGM region into permanent hematopoiesis in bone marrow via fetal liver. Furthermore, precursor cells of T cells and thymus dendritic cells migrate from the fetal liver into the bone marrow and then into the thymus gland and cytodifferentiate under thymus environment. The T cell which received clone selection migrates into secondary lymphoid tissues and takes part in an immune response in the periphery. The Langerhans' cell of the skin activated and differentiated by capturing an antigen migrates into the T cell region of a topical lymph node and activates naive T cell therein as a dendritic cell. The memory T cell performs its homing again into the lymph node via lymphatic and blood vessels. Also, B cell, T cell in the intestinal epithelium, γδ T cell, NKT cell and dendritic cell migrate from bone marrow without passing through the thymus gland and differentiate to take part in an immune response.
Chemokine deeply takes part in the migration of such various cells. Chemokine receptors are greatly related to the control of inflammation and immune responses through a mechanism in which they are expressed at certain specified periods in variously specific cells and the effector cells are accumulated in a region where chemokine is produced.
For example, it is reported an investigation in animal models such as CCR5-knockout mouse suggesting that CCR5 as a chemokine receptor plays a significant role in rejection in organ transplantation or autoimmune disease, etc. (Transplantation, Vol. 72(7), 1199-1205 (2001); Diabetes, Vol. 51(8), 2489-2495 (2002); Journal of Virology, Vol. 77(1), 191-198 (2003); Journal of Immunology, Vol. 164(12), 6303-6312 (2000)). It is also reported which make a comparison a risk of developing several diseases and a length of the survival of the transplanted graft, etc. between a human having inactive CCR and a human having wild-type one (Ref. The Lancet, Vol. 357, 1758-1761 (2001); Arthritis & Rheumatism, Vol. 42(5), 989-992 (1999); The Lancet, Vol. 354, 1264-1265 (1999); European Journal of Immunogenetics, Vol. 29(6) 525-528 (2002)). It is suggested that CCR5 is related to several diseases, but they make no reference to the effect of drugs which antagonizes CCR in their reports.
At present, immunosuppressive treatment for diseases in transplantation area is provided. That is, a calcineurin inhibitor such as cyclosporin or tacrolimus (FK506) is used mainly with various type of an immunosuppressant agent, for example, a TOR (target of rapamycin) inhibitor such as sirolimus (rapamycin), a non-specific antiphlogistic such as corticosteroids, an antiproliferative drug such as azathioprine, mycophenolate mofetil, etc. But, it frequently causes a chronic rejection or a severe side effect, so it is desired a useful novel immunosuppressant agent which prolongs a length of the survival of the transplanted graft and reduces the side effects in comparison with existing drugs.
An antiinflammatory drug or a drug which modulates immune function such as nonsteroidal antiinflammatory drug (NSAIDs) which have an inhibitory activity against cyclooxygenase (COX), disease modifying anti-rheumatic drug (DMARDs), steroids, etc. is used for treatment for autoimmune disease or allergic diseases. The more effective a drug is, the severer a side effect caused by it is, and it is suggested that the treatment with these drugs is not an underlying remedy for the disease, but a mere symptomatic treatment.
At the same time, acquired immunodeficiency syndrome (hereinafter referred to as “AIDS”) which is induced by human immunodeficiency virus (hereinafter referred to as “HIV”) is one of the diseases of which their therapeutic methods are most earnestly desired in recent years. Once infection with HIV is completed in a CD4-positive cell which is a principal target cell, HIV repeats its proliferation in the body of the patient and, sooner or later, completely destroys T cell which takes charge of the immunological function. During this process, the immunological function is gradually reduced to cause fever, diarrhea, lymph node enlargement and the like various immunodeficiency conditions which are apt to cause complications with pneumocystis carinii pneumonia and the like various opportunistic infections. Such conditions are the onset of AIDS, and it is well known that they induce and worsen Kaposi sarcoma and the like malignant tumors.
As the recent preventive and/or therapeutic methods for AIDS, attempts have been made to, e.g., (1) inhibit growth of HIV by the administration of a reverse transcriptase inhibitor or a protease inhibitor and (2) prevent or alleviate opportunistic infections by the administration of a drug having immunopotentiation activity.
Helper T cells which take charge of the central of immune system are mainly infected with HIV. It is known since 1985 that HIV uses the membrane protein CD4 expressing on the membrane of T cells in the infection (Cell, 52, 631 (1985)). The CD4 molecule is composed of 433 amino acid residues, and its expression can be found in macrophages, some B cells, vascular endothelial cells, Langerhans' cells in skin tissues, dendritic cells in lymphoid tissues, glia cells of the central nervous system and the like, in addition to the mature helper T cells. However, since it has been revealed that the infection with HIV is not completed by the CD4 molecule alone, a possibility has been suggested on the presence of factors other than the CD4 molecule, which are related to the infection of cells with HIV.
CCR5, which is a receptor of RANTES, MIP-1α and MIP-1β, is also used at the time of the infection with a macrophage tropic (R5) HIV (Science, 272, 1955 (1996)).
Accordingly, substances which can compete with CCR5 for HIV, or which can bind to HIV virus thus causing the virus unable to bind to CCR5, could become HIV infection inhibitors.
It is also reported a possibility that the CCR5 is used in the infection with Respiratory Syncytial Virus (hereinafter referred to as “RSV”).
It is reported that CCR5 are expressed in arteriosclerotic plaque, so it is considered that chemokine receptor modulators are also useful in treating cardiovascular diseases.
Based on the above, it is considered that chemokine (for example, RANTES, MIP-1α (, MIP-1β, etc.) receptors, especially CCR5 are deeply related to the inflammation, immunological diseases, infectious diseases (infection with HIV, infection with RSV, etc.), and cardiovascular diseases. For example, it is considered that they are related to various inflammatory diseases (asthma, nephritis, nephropathy, hepatitis, arthritis, rheumatoid arthritis, rhinitis, conjunctivitis, inflammatory bowel disease such as ulcerative colitis, etc.), immunological diseases (autoimmune diseases, rejection in organ transplantation (rejection of graft of solid organ, rejection of graft of pancreatic islet cells in therapy for diabetes, graft-versus-host disease, etc.), immunosuppression, psoriasis, multiple sclerosis, etc.), infectious diseases (infection with human immunodeficiency virus, acquired immunodeficiency syndrome, infection with RSV, etc.), allergic diseases (atopic dermatitis, urticaria, allergic bronchopulmonary aspergillosis, allergic eosinophilic gastroenteritis, etc.), cardiovascular diseases (arteriosclerosis, ischemic reperfusion injury, etc.), acute respiratory distress syndrome, shock accompanying bacterial infection, diabetes mellitus, cancer metastasis and the like.
It is reported that the aminopiperidine derivatives represented by formula (Z)
(wherein R1Z is hydrogen atom or C1-12 alkyl, R2Z and R3Z are each independently hydrogen atom or C1-12 alkyl, XZ is nitrogen atom or oxygen atom, AZ is
(wherein R4Z is hydrogen atom, C1-12 alkyl, C3-8 cycloalkyl, aryl, substituted aryl, aryl-C(═O)— or aryl-CH(OH)—, R5Z is hydrogen, C1-12 alkyl, C1-4 alkoxy, halogen or COR, R6Z is hydrogen, C1-12 alkyl or substituted C1-4 alkyl. With the proviso that the definition of each symbol is an excerpt partially.) are useful as inhibitors of the chemokine receptors (ref specification of WO02/079186).
It is described that the sulfonic acid compounds represented by formula (W)
(wherein XW is —O—, —S—, —CH2— or —NR6—, YW is C6-10 aryl or C2-9 heteroaryl, R1W is selected from the group consisting of: H—, HO—, halo-, C1-8 alkyl- optionally substituted with 1-3 fluorine atoms, etc., R2W and R3W is selected from the group consisting of: H—, oxo, C1-8 alkyl- optionally substituted with 1-3 fluorine atoms, etc., R4W is selected from the group consisting of: H—, HO—, halo-, NC—, etc., R5W is C1-8 alkyl, aW is 0-5, bW is 0-2, cW is 0-2, and dW is 0-4. With the proviso that the definition of each symbol is an excerpt partially.), pharmacological acceptable salts thereof and prodrugs thereof are selective antagonists of CCR1 (ref specification of WO02/102787).
Moreover, 1-(4-pyridyl)-piperazine derivatives are described as CCR5 antagonists (ref specification of U.S. Pat. No. 6,391,865).
On the other hand, it is reported that triazaspiro[5.5]undecane derivatives, quaternary ammonium salts thereof or N-oxides thereof, or pharmacologically acceptable salts thereof regulate the effect of chemokine/chemokine receptor, so they are used for prevention and/or treatment of various inflammatory diseases, asthma, atopic dermatitis, urticaria, allergic diseases (allergic bronchopulmonary aspergillosis or allergic eosinophilic gastroenteritis etc.), nephritis, nephropathy, hepatitis, arthritis, rheumatoid arthritis, psoriasis, rhinitis, conjunctivitis, ischemic reperfusion disorder, multiple sclerosis, ulcerative colitis, acute respiratory distress syndrome, cytotoxic shock, diabetes, autoimmune disease, in transplanted organ rejection reactions, immunosuppression, cancer metastasis and acquired immune deficiency syndrome (ref specification of WO01/40227).
It is described that the compounds represented by formula (M)
(wherein mM and nM, which are the same or different, is each zero or the integer 1 or 2, Alk3M is a covalent bond or a straight or branched C1-6 alkylene chain, R1M and R2M, which are the same or different, is each a hydrogen atom or a straight or branched C1-6 alkyl group, DM is an optionally substituted aromatic or heteroaromatic ring group, EM is an optionally substituted C7-10 cycloalkyl, C7-10 cycloalkenyl or C7-10 polycycloaliphatic group.) are modulators of CXCR3 (ref specification of WO03/070242).